X-Message-Number: 11659
Date: Sat, 01 May 1999 21:07:12 -0400
From: Jan Coetzee <>
Subject: New Brains

BOSTON (AP) -- Scientists want to fix the things that go wrong inside
your
head. Their plan: Grow replacement parts for broken brains. They make it

sound easy. Just brew a batch of gray matter. Drill a hole in the skull.

Put
in the new stuff. Wire it up like the original. Voila! New brains.

Despite its whiff of mad scientist run amok, this scenario is
surprisingly
close to reality. Researchers can already do amazing things with mouse
brains. And as they so fondly and frequently point out, mice really are
an
awful lot like us.

Some human experiments already hint at what's possible. Since the 1980s,

doctors have cautiously tested transferring brain cells from aborted
fetuses
to victims of Parkinson's disease. For some, it seems to work remarkably

well, restoring lost control of movement. But to those on the cusp of
this
new technology, Parkinson's is almost too easy. It involves the death of

just
one small bit of material, the brain cells that make the
message-carrying
neurotransmitter dopamine. No, they have their sights on much more
complicated targets. In the years to come, they see the possibility of
rewiring broken spines, patching up strokes, correcting multiple
sclerosis,
undoing inherited metabolic disorders, maybe even rebuilding the wrecked

brains of Alzheimer's disease victims.

``I mean not just putting in cells to produce a neurotransmitter or make
a
little local connection,'' explains Dr. Jeffrey Macklis of Children's
Hospital and Harvard Medical School in Boston. ``I mean really rewiring
complex circuitry in the brain. Ten years ago, this would have been
considered totally crazy. Five years ago, it would have been a little
bonkers.'' Macklis goes on to talk about his mice, the critters of
choice
for
those who study such things. When immature cells are transplanted under
precisely the right conditions, they migrate across the animals' tiny
damaged
brains. They take root in just the spots where they are needed. They
morph
into the exact brands of cells that are missing. They connect up with
other
parts of the brain. In short, they seem to work.

``Mice brains are fundamentally not that different from humans','' says
Macklis. ``The idea of using immature cells and guiding their
differentiation
to rebuild complex circuitry is no longer crazy.'' Until recently, human

fetuses were the only source of brain material for such jobs, but they
were
never ideal. Doctors' qualms go beyond the ethical thickets of recycling

aborted material. Fetuses will always be in short supply; it takes
several
to
treat just one patient. And quality is hard to control, especially
considering that many were aborted for a reason, such as genetic
abnormalities.

But now scientists seem certain that transplanting brain material --
what
they call cell therapy -- is about to become practical. The reason is
the
discovery of entirely new reservoirs of brain material. At dozens of
universities and biotech firms, they are developing three main varieties
--
animal brains, cancerous growths and the tissue wellspring called stem
cells.
One of these sources can be found at a gleaming biomedical lab off a
country
road about 60 miles west of Boston. The first thing that makes the place

seem
a little odd is the technicians' get-ups: green surgical scrubs with
knee-high black rubber boots. Then there's the smell. Despite fans that
turn
over the air 19 times an hour and filter it cleaner than an operating
room's,
the lab carries a certain barnyard redolence, an unmistakable eau de
pig.
This lab is also a barn, home to 65 or so grunting, rooting animals. But

the
end product is brain parts, not pork chops.

``This is literally the cleanest pig facility on the face of the
earth,''
says David Boucher, the veterinary technician who makes sure the walls
sparkle, the germs stay far away and the animals themselves enjoy
unpiglike
spotlessness. It may be the world's most expensive pig facility, too.
The
275-pound Yorkshire sows -- ``the girls,'' Boucher affectionately calls
them
-- cost between $20,000 and $30,000 apiece to raise this way. However,
the
price will fall dramatically if pig cells are approved for routine human

medical use, and production scales up.

When it's time for a still-experimental transplant, the technicians kill

three artificially inseminated pigs that have been pregnant exactly 27
days.
Then they surgically remove their fetuses. (Killing the sows, they say,
is
the only way to get the unborn pigs out antiseptically.) It takes the
brains
of 26 pig fetuses to gather 48 million dopamine-producing cells, enough
for
one person with Parkinson's. The cells are shipped to a hospital, and
less
than 72 hours later, they are inside someone's brain. So far, these pig
cells
have been tested on 20 people with Parkinson's, six with epilepsy and
six
with Huntington's disease. Of the first 11 Parkinson's patients treated,

three improved significantly.

``I have no doubt this can work and produce tremendous benefit,'' says
Dr.
Greg Stewart of Genzyme, which is developing the treatment with Diacrin,

another biotech firm. While the supply of fetal pig cells is not a
problem,
there are other drawbacks. Patients may need to take immune-suppressing
drugs
to keep their bodies from rejecting the tissue, and there is a remote
chance
that dangerous animal viruses might be passed along. ``I don't think
it's
an
elegant way to solve the problem,'' says Dr. Michael Levesque of
Cedars-Sinai
Medical Center in Los Angeles. A bit more elegant, perhaps, is a method
being
tested at the University of Pittsburgh. Doctors there are experimentally

transplanting human cells into the brains of stroke victims. The cells
are
similar to stem cells, the factories that manufacture various kinds of
tissue
inside the body. But there's a catch: These cells began as cancer, grown
in
test tubes from a 22-year-old's testicular tumor.

The transplants are being tested on 12 stroke victims. All suffer
paralysis
or other serious disability, even though the strokes destroyed only a
small
bit of their brain tissue. Three seem to have improved. One walks
better,
another is less stiff, while a third has better control of arm and leg
movements. Are the extra cells responsible? Or is this the natural
course
of
recovery? Dr. Douglas Kondziolka, the surgeon in charge, does not know.
Still, he says, ``We were hoping for a glimmer of efficacy so we could
continue on. We've seen even a little more than a glimmer.''

Fixing a stroke, however, is far more challenging than relieving
Parkinson's.
A stroke leaves a dead zone inside the brain. Missing are many kinds of
cells
that were hooked up in complex patterns. In their attempt at repair,
surgeons
add their cancer-derived cells to the ring of damaged tissue that
surrounds
the dead area. Just why this might do some good isn't completely clear.
But
the doctors speculate that the new cells help the hurt ones by restoring

connections, releasing neurotransmitters and pumping in amino acids.

As best they can tell, the transplanted cells have been transformed from

cancerous gonadal cells to stable nerve cells through a series of
manipulations. But the idea of using cancer cells makes some doctors
uneasy.
Others worry that the challenges of repairing strokes are just too vast
to
even attempt yet.

``I do believe that we will be able to treat strokes and the more
complicated
disorders. I just don't think we're ready to do that yet,'' cautions Dr.

John
Kessler of Albert Einstein College of Medicine in New York City. Many
agree
that the most elegant solution of all to the supply problem is stem
cells.
These are the body's mother cells. They divide over and over to form new

tissue, such as blood cells and skin. For generations, scientific dogma
held
that the adult brain cannot repair itself, because it lacks stem cells.
Wrong. Recently, scientists found that adult brains do indeed harbor
stem
cells, although their exact function is still a mystery. But when coaxed

properly in a test tube, they will divide over and over again, making
brand-new neurons. Suddenly, it seems, cancer cells and animal cells may
be
unnecessary. The real thing, human brain cells, will be available. But
what
kind of stem cell is the proper seed?

Since stem cells divide endlessly, a single sample started from a human
fetus
could provide all that's needed. But the recipient's immune system might

attack these as foreign. Perhaps the patient's own body is a better
source
of
stem cells.
At Cedars-Sinai, scientists isolate stem cells from tissue saved during
brain
operations on Parkinson's patients. In the lab, these stem cells produce

new
brain cells. These in turn mature into dopamine makers, the specific
kind
of
brain cells that people with Parkinson's lack. Finally, they are put
back
into the patients' brains. Even if this works, however, the approach has
an
obvious shortcoming. The only source of these brain stem cells is the
patient's own brain, not a particularly accessible reservoir. However,
brain
stem cells may not be a necessary ingredient for custom-making new brain

tissue. Scientists believe it may be possible to reprogram more readily
available kinds of stem cells, such as the ones that produce skin, so
that
they will churn out brain cells, instead.

But are transplants necessary at all? Maybe not. Repairs might actually
be
engineered by remote control without ever putting anything into the
head.
Some scientists talk of stimulating the stem cells still inside the
brain
so
they divide and send off new nerve cells. Farfetched as this sounds,
they
say
it may be possible to direct the cells to travel to distant parts of the

brain and then take on the specialized duties of cells that are missing
or
damaged. Still, to cure a stroke or head injury, a reliable supply of
brain
cells is just the start. Somehow they must be wired up so each
communicates
with its neighbor in a sensible way. ``The biggest hurdle is not getting

cells into the nervous system,'' says Kessler. ``It's not getting them
to
differentiate and to live. The biggest hurdle is getting them to
reconnect
in
the proper way. That is an extraordinarily daunting process, when you
think
of the billions of connections that have to be formed.''

Yet scientists such as Macklis and Dr. Evan Snyder, a Children's
Hospital
colleague, think this is entirely possible. For one thing, their
experiments
suggest that damaged parts of the brain send out help signals that can
recruit transplanted cells and show them what to do. In mice, at least,
immature neurons injected into the head will travel across the brain to
where
cells are dying. There they assume the form of the missing cells,
stitching
themselves seamlessly into the brain's circuitry. Cells injected into
the
brain's fluid-filled ventricles eventually migrate all through the head.

The
researchers say such an approach might eventually conquer diseases that
involve many parts of the brain. The whole idea of bringing in
replacement
cells from someplace else grew out the belief that the brain cannot
repair
itself. But with the discovery of brain stem cells, that dogma is
crumbling.

``Cell therapy might be even more interesting, not less,'' says Snyder.
``Not
only might it mean we put back cells that the brain does not grow on its

own,
but maybe we will do it by augmenting a natural response.'' In short,
these
scientists envision a day when repairing a broken brain will involve no
transplants, no operations. Instead, it will mean triggering the brain
to
awaken its supply of stem cells, to grow its own spare parts, to
literally
fix itself.

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